Natural and synthetic retinoids (vitamin A derivatives) may provide a new approach to the prevention and therapy of epithelial cancer. These agents appear to block premalignant metaplasia by maintaining tissues in a differentiated state, yet the mechanism of their action remains unknown. That retinoids directly alter both plasma and intracellular membranes is well known, but the recent description of distinct cytosol receptors for retinol and retinoic acid in several mammalian tissues suggests a steroid-like effect as well. Using the readily accessible human tumor, cutaneous basal cell carcinoma, we will examine the structural alterations which accompany tumor regression during topical retinoid therapy. Previous studies have demonstrated that a majority of these tumors will respond to topical retinoid therapy. Several lesions on the same patient will be treated with retinoic acid, retinol, 5-fluorouracil, and vehicle in a double-blind controlled fashion. A known quantity of each substance will be delivered to each lesion, and documentation of penetration will be obtained utilizing the vitamin's known capacity to autofluoresce. Biopsies will be obtained prior to therapy and after one week. Specimens will be analyzed for changes in intercellular junctions, plasma membrane integral particle organization, actin microfilaments, and basement membrane-hemidesmosome structure utilizing routine thin sections, freeze-fracture replicas, and stereological (morphometric) methods. Furthermore, short-term incubations with retinoic acid will be employed in order to more specifically pinpoint the primary effects of vitamin A from the multiple, secondary responses which occur in vivo. By identifying the principal targets of retinoid action in basal cell carcinoma, the study should provide greater understanding of carcinogenesis and tumor regression in general.